Non-small cell lung cancer, CNS metastases

From HemOnc.org - A Hematology Oncology Wiki
Jump to navigation Jump to search

Back to Top

Page editor Section editor
Singhi Eric.jpeg
 Eric K. Singhi, MD
MD Anderson Cancer Center
Houston, TX, USA
LinkedIn
Amit Kulkarni.jpg
 Amit Kulkarni, MBBS
University of Minnesota
Minneapolis, MN, USA
LinkedIn
15 regimens on this page
17 variants on this page

Note: these are studies of regimens tested in patients with NSCLC and CNS metastases, or subgroups of more general studies that focused on patients with CNS metastases. Please see the main NSCLC page for other regimens.


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

NCCN

All lines of therapy

Cisplatin & Vinorelbine (CVb)

CVb: Cisplatin & Vinorelbine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Robinet et al. 2001 (GFPC 95-1) 1995-1997 Phase 3 (C) CVb & concurrent WBRT Did not meet primary endpoint of OS6

Chemotherapy

28-day cycle for 6 cycles

Subsequent treatment

References

  1. GFPC 95-1: Robinet G, Thomas P, Breton JL, Léna H, Gouva S, Dabouis G, Bennouna J, Souquet PJ, Balmes P, Thiberville L, Fournel P, Quoix E, Riou R, Rebattu P, Pérol M, Paillotin D, Mornex F. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Français de Pneumo-Cancérologie (GFPC) Protocol 95-1. Ann Oncol. 2001 Jan;12(1):59-67. link to original article contains dosing details in abstract PubMed

Dexamethasone monotherapy

Regimen

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Mulvenna et al. 2016 (QUARTZ) Phase 3 (E-de-esc) Dexamethasone & WBRT Inconclusive whether non-inferior QALYs (primary endpoint)

Supportive therapy

References

  1. QUARTZ: Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, Moore B, Brisbane I, Ardron D, Holt T, Morgan S, Lee C, Waite K, Bayman N, Pugh C, Sydes B, Stephens R, Parmar MK, Langley RE. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016 Oct 22;388(10055):2004-2014. Epub 2016 Sep 4. link to original article link to PMC article PubMed ISRCTN3826061

Dexamethasone & WBRT

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Mulvenna et al. 2016 (QUARTZ) 2007-03-02 to 2014-08-29 Phase 3 (C) Dexamethasone Inconclusive whether non-inferior QALYs

Radiotherapy

  • WBRT, 2000 cGy in 5 fractions

Supportive therapy

References

  1. QUARTZ: Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, Moore B, Brisbane I, Ardron D, Holt T, Morgan S, Lee C, Waite K, Bayman N, Pugh C, Sydes B, Stephens R, Parmar MK, Langley RE. Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet. 2016 Oct 22;388(10055):2004-2014. Epub 2016 Sep 4. link to original article link to PMC article PubMed ISRCTN3826061

Teniposide monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Postmus et al. 2000 1989-1995 Phase 3 (C) Teniposide & RT Might have inferior OS

Chemotherapy

21-day cycle for up to 12 cycles

References

  1. Postmus PE, Haaxma-Reiche H, Smit EF, Groen HJ, Karnicka H, Lewinski T, van Meerbeeck J, Clerico M, Gregor A, Curran D, Sahmoud T, Kirkpatrick A, Giaccone G; European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy--a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol. 2000 Oct 1;18(19):3400-8. link to original article contains dosing details in manuscript PubMed

Teniposide & WBRT

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Postmus et al. 2000 1989-1995 Phase 3 (E-esc) Teniposide Might have superior OS

Chemotherapy

21-day cycle for up to 12 cycles

Radiotherapy

  • WBRT, 3000 cGy in 10 fractions

References

  1. Postmus PE, Haaxma-Reiche H, Smit EF, Groen HJ, Karnicka H, Lewinski T, van Meerbeeck J, Clerico M, Gregor A, Curran D, Sahmoud T, Kirkpatrick A, Giaccone G; European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy--a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol. 2000 Oct 1;18(19):3400-8. link to original article contains dosing details in manuscript PubMed

Whole brain irradiation

WBRT: Whole-Brain Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2021 (ENTER) 2013-08-07 to 2016-11-25 Phase 3 (C) Erlotinib & WBRT Did not meet primary endpoint of intracranial PFS

Radiotherapy

One course

References

  1. ENTER: Yang Z, Zhang Y, Li R, Yisikandaer A, Ren B, Sun J, Li J, Chen L, Zhao R, Zhang J, Xia X, Liao Z, Carbone DP. Whole-brain radiotherapy with and without concurrent erlotinib in NSCLC with brain metastases: a multicenter, open-label, randomized, controlled phase III trial. Neuro Oncol. 2021 Jun 1;23(6):967-978. link to original article link to PMC article PubMed NCT01887795

ALK-mutated, all lines of therapy

Alectinib monotherapy

Regimen variant #1, 300 mg twice per day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hida et al. 2017 (J-ALEX) 2013-2015 Phase 3 (E-switch-ic) Crizotinib Superior TTP1 (secondary endpoint)

1Reported CNS efficacy is based on the 2018 update.
This is the PMDA-approved dose in Japan.

Biomarker eligibility criteria

  • Gene ALK positive

Targeted therapy

Continued indefinitely


Regimen variant #2, 600 mg twice per day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Peters et al. 2017 (ALEX) 2014-2016 Phase 3 (E-switch-ic) Crizotinib Superior TTP1 (secondary endpoint)

1Reported CNS efficacy is based on the 2018 update.

Biomarker eligibility criteria

  • Gene ALK positive

Targeted therapy

Continued indefinitely

References

  1. J-ALEX: Hida T, Nokihara H, Kondo M, Kim YH, Azuma K, Seto T, Takiguchi Y, Nishio M, Yoshioka H, Imamura F, Hotta K, Watanabe S, Goto K, Satouchi M, Kozuki T, Shukuya T, Nakagawa K, Mitsudomi T, Yamamoto N, Asakawa T, Asabe R, Tanaka T, Tamura T. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017 Jul 1;390(10089):29-39. Epub 2017 May 10. link to original articlecontains dosing details in abstractPubMed JapicCTI-132316
    1. Subgroup analysis: Nishio M, Nakagawa K, Mitsudomi T, Yamamoto N, Tanaka T, Kuriki H, Zeaiter A, Tamura T. Analysis of central nervous system efficacy in the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer. Lung Cancer. 2018 Jul;121:37-40. Epub 2018 Apr 17. link to original article PubMed
  2. ALEX: Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, Ou SI, Pérol M, Dziadziuszko R, Rosell R, Zeaiter A, Mitry E, Golding S, Balas B, Noe J, Morcos PN, Mok T; ALEX Trial Investigators. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017 Aug 31;377(9):829-838. Epub 2017 Jun 6. link to original article contains dosing details in manuscript PubMed NCT02075840
    1. Subgroup analysis: Gadgeel S, Peters S, Mok T, Shaw AT, Kim DW, Ou SI, Pérol M, Wrona A, Novello S, Rosell R, Zeaiter A, Liu T, Nüesch E, Balas B, Camidge DR. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol. 2018 Nov 1;29(11):2214-2222. link to original article link to PMC article PubMed

Ceritinib monotherapy

Regimen

Study Dates of enrollment Evidence
Shaw et al. 2014 (ASCEND-1) 2011-2013 Phase 1, >20 pts in this dosing cohort

Note: CNS efficacy is based on the 2016 update.

Biomarker eligibility criteria

Targeted therapy

21-day cycles

References

  1. ASCEND-1: Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Lau YY, Goldwasser M, Boral AL, Engelman JA. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Mar 27;370(13):1189-97. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01283516
    1. Update: Kim DW, Mehra R, Tan DSW, Felip E, Chow LQM, Camidge DR, Vansteenkiste J, Sharma S, De Pas T, Riely GJ, Solomon BJ, Wolf J, Thomas M, Schuler M, Liu G, Santoro A, Sutradhar S, Li S, Szczudlo T, Yovine A, Shaw AT. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol. 2016 Apr;17(4):452-463. Epub 2016 Mar 11. link to original article link to PMC article PubMed

Crizotinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hida et al. 2017 (J-ALEX) 2013-2015 Phase 3 (C) Alectinib Inferior TTP1 (secondary endpoint)
Peters et al. 2017 (ALEX) 2014-2016 Phase 3 (C) Alectinib Inferior TTP2 (secondary endpoint)

1Reported CNS efficacy for J-ALEX is based on the 2018 update.
2Reported CNS efficacy for ALEX is based on the 2018 update.

Biomarker eligibility criteria

  • Gene ALK positive

Targeted therapy

28-day cycles

References

  1. J-ALEX: Hida T, Nokihara H, Kondo M, Kim YH, Azuma K, Seto T, Takiguchi Y, Nishio M, Yoshioka H, Imamura F, Hotta K, Watanabe S, Goto K, Satouchi M, Kozuki T, Shukuya T, Nakagawa K, Mitsudomi T, Yamamoto N, Asakawa T, Asabe R, Tanaka T, Tamura T. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017 Jul 1;390(10089):29-39. Epub 2017 May 10. link to original articlecontains dosing details in abstractPubMed JapicCTI-132316
    1. Subgroup analysis: Nishio M, Nakagawa K, Mitsudomi T, Yamamoto N, Tanaka T, Kuriki H, Zeaiter A, Tamura T. Analysis of central nervous system efficacy in the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer. Lung Cancer. 2018 Jul;121:37-40. Epub 2018 Apr 17. link to original article PubMed
  2. ALEX: Peters S, Camidge DR, Shaw AT, Gadgeel S, Ahn JS, Kim DW, Ou SI, Pérol M, Dziadziuszko R, Rosell R, Zeaiter A, Mitry E, Golding S, Balas B, Noe J, Morcos PN, Mok T; ALEX Trial Investigators. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017 Aug 31;377(9):829-838. Epub 2017 Jun 6. link to original article contains dosing details in manuscript PubMed NCT02075840
    1. Subgroup analysis: Gadgeel S, Peters S, Mok T, Shaw AT, Kim DW, Ou SI, Pérol M, Wrona A, Novello S, Rosell R, Zeaiter A, Liu T, Nüesch E, Balas B, Camidge DR. Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer: CNS efficacy results from the ALEX study. Ann Oncol. 2018 Nov 1;29(11):2214-2222. link to original article link to PMC article PubMed

EGFR-mutated, all lines of therapy

Afatinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sequist et al. 2013 (LUX-Lung 3) 2009-2011 Phase 3 (E-switch-ooc) Cisplatin & Pemetrexed Seems to have superior PFS1 (secondary endpoint)
Wu et al. 2014 (LUX-Lung 6) 2010-2011 Phase 3 (E-switch-ooc) Cisplatin & Gemcitabine Seems to have superior PFS1 (secondary endpoint)

1Reported CNS-specific efficacy is based on the 2016 subgroup analysis.

Biomarker eligibility criteria

  • Gene EGFR mutation (Leu858Arg, exon 19 deletions, or other)

Targeted therapy

  • Afatinib (Gilotrif) 40 mg PO once per day, taken 1 hour before eating food (LUX-Lung 2: "no food intake immediately before or after afatinib")

Continued indefinitely

Dose and schedule modifications

  • LUX-Lung 3: Afatinib (Gilotrif) could be increased to 50 mg PO once per day if patients did not experience any grade 2 or higher rash, diarrhea, mucositis, or other drug-related adverse event.

References

  1. LUX-Lung 3: Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3327-34. Epub 2013 Jul 1. link to original article contains dosing details in manuscript PubMed NCT00949650
    1. HRQoL analysis: Yang JC, Hirsh V, Schuler M, Yamamoto N, O'Byrne KJ, Mok TS, Zazulina V, Shahidi M, Lungershausen J, Massey D, Palmer M, Sequist LV. Symptom control and quality of life in LUX-Lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3342-50. Epub 2013 Jul 1. link to original article contains dosing details in manuscript PubMed
    2. Pooled update: Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. link to original article PubMed
    3. Pooled subgroup analysis: Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, Yamamoto N, Yu CJ, Ou SH, Zhou C, Massey D, Zazulina V, Wu YL. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015 Jul;16(7):830-8. Epub 2015 Jun 4. link to original article PubMed
    4. Subgroup analysis: Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. link to original article PubMed
  2. LUX-Lung 6: Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee KY, Xu CR, Massey D, Kim M, Shi Y, Geater SL. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):213-22. link to original article contains dosing details in manuscript PubMed NCT01121393
    1. Pooled update: Yang JC, Wu YL, Schuler M, Sebastian M, Popat S, Yamamoto N, Zhou C, Hu CP, O'Byrne K, Feng J, Lu S, Huang Y, Geater SL, Lee KY, Tsai CM, Gorbunova V, Hirsh V, Bennouna J, Orlov S, Mok T, Boyer M, Su WC, Lee KH, Kato T, Massey D, Shahidi M, Zazulina V, Sequist LV. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015 Feb;16(2):141-51. link to original article PubMed
    2. Pooled subgroup analysis: Yang JC, Sequist LV, Geater SL, Tsai CM, Mok TS, Schuler M, Yamamoto N, Yu CJ, Ou SH, Zhou C, Massey D, Zazulina V, Wu YL. Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. Lancet Oncol. 2015 Jul;16(7):830-8. Epub 2015 Jun 4. link to original article PubMed
    3. Subgroup analysis: Schuler M, Wu YL, Hirsh V, O'Byrne K, Yamamoto N, Mok T, Popat S, Sequist LV, Massey D, Zazulina V, Yang JC. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. link to original article PubMed

Cisplatin, Gefitinib, Pemetrexed

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hou et al. 2023 (GAP BRAIN) 2016-2021 Phase 3 (E-esc) Gefitinib Superior intracranial PFS (primary endpoint)
Median intracranial PFS: 15.6 vs 9.1 mo
(HR 0.36, 95% CI 0.25-0.53)

Seems to have superior OS (secondary endpoint)
Median OS: 35 vs 28.9 mo
(HR 0.65, 95% CI 0.43-0.99)

Biomarker eligibility criteria

  • EGFR exon 19 deletion or exon 21 L858R mutation

Chemotherapy

Targeted therapy

28-day cycles

References

  1. GAP BRAIN: Hou X, Li M, Wu G, Feng W, Su J, Jiang H, Jiang G, Chen J, Zhang B, You Z, Liu Q, Chen L. Gefitinib Plus Chemotherapy vs Gefitinib Alone in Untreated EGFR-Mutant Non-Small Cell Lung Cancer in Patients With Brain Metastases: The GAP BRAIN Open-Label, Randomized, Multicenter, Phase 3 Study. JAMA Netw Open. 2023 Feb 1;6(2):e2255050. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01951469

Gefitinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hou et al. 2023 (GAP BRAIN) 2016-2021 Phase 3 (C) 1a. Cisplatin, Gefitinib, Pemetrexed
1b. Gefitinib, Nedaplatin, Pemetrexed 		Inferior intracranial PFS

Biomarker eligibility criteria

  • EGFR exon 19 deletion or exon 21 L858R mutation

Targeted therapy

Continued indefinitely

References

  1. GAP BRAIN: Hou X, Li M, Wu G, Feng W, Su J, Jiang H, Jiang G, Chen J, Zhang B, You Z, Liu Q, Chen L. Gefitinib Plus Chemotherapy vs Gefitinib Alone in Untreated EGFR-Mutant Non-Small Cell Lung Cancer in Patients With Brain Metastases: The GAP BRAIN Open-Label, Randomized, Multicenter, Phase 3 Study. JAMA Netw Open. 2023 Feb 1;6(2):e2255050. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01951469

Gefitinib, Nedaplatin, Pemetrexed

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hou et al. 2023 (GAP BRAIN) 2016-2021 Phase 3 (E-esc) Gefitinib Superior intracranial PFS (primary endpoint)
Median intracranial PFS: 15.6 vs 9.1 mo
(HR 0.36, 95% CI 0.25-0.53)

Seems to have superior OS (secondary endpoint)
Median OS: 35 vs 28.9 mo
(HR 0.65, 95% CI 0.43-0.99)

Biomarker eligibility criteria

  • EGFR exon 19 deletion or exon 21 L858R mutation

Chemotherapy

Targeted therapy

28-day cycles

References

  1. GAP BRAIN: Hou X, Li M, Wu G, Feng W, Su J, Jiang H, Jiang G, Chen J, Zhang B, You Z, Liu Q, Chen L. Gefitinib Plus Chemotherapy vs Gefitinib Alone in Untreated EGFR-Mutant Non-Small Cell Lung Cancer in Patients With Brain Metastases: The GAP BRAIN Open-Label, Randomized, Multicenter, Phase 3 Study. JAMA Netw Open. 2023 Feb 1;6(2):e2255050. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01951469

Icotinib monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2017 (BRAIN) 2012-2015 Phase 3 (E-switch-ooc) WBRT Seems to have superior intracranial PFS (primary endpoint)

Note: this drug is only approved in China.

Biomarker eligibility criteria

  • EGFR Mutation
  • Clinical Trial Eligibility: EGFR Exon 19 deletion, EGFR exon 21 L858R, Uncommon EGFR mutations

Targeted therapy

Continued indefinitely

References

  1. BRAIN: Yang JJ, Zhou C, Huang Y, Feng J, Lu S, Song Y, Huang C, Wu G, Zhang L, Cheng Y, Hu C, Chen G, Zhang L, Liu X, Yan HH, Tan FL, Zhong W, Wu YL. Icotinib versus whole-brain irradiation in patients with EGFR-mutant non-small-cell lung cancer and multiple brain metastases (BRAIN): a multicentre, phase 3, open-label, parallel, randomised controlled trial. Lancet Respir Med. 2017 Sep;5(9):707-716. Epub 2017 Jul 19. link to original article contains dosing details in abstract PubMed NCT01724801

Osimertinib monotherapy

Regimen variant #1, 80 mg/day

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jänne et al. 2015 (AURA) 2013-NR Phase 1/2 (RT)
Goss et al. 2016 (AURA2) 2014 Phase 2 (RT)
Mok et al. 2016 (AURA3) 2014-08 to 2015-09 Phase 3 (E-switch-ooc) 1a. Carboplatin & Pemetrexed
1b. Cisplatin & Pemetrexed 		Seems to have superior ORR1 (secondary endpoint)
Soria et al. 2017 (FLAURA) 2014-2016 Phase 3 (E-switch-ic) 1a. Erlotinib
1b. Gefitinib 		Seems to have superior PFS2 (secondary endpoint)
Yamaguchi et al. 2021 (WJOG9116L) 2016-2019 Phase 2

1Reported efficacy for AURA3 is based on the 2018 subgroup analysis.
2Reported efficacy for FLAURA is based on the 2018 subgroup analysis.
Note: Patients enrolled in AURA3 had locally advanced or metastatic NSCLC with progression after first-line EGFR TKI therapy. CNS efficacy for AURA & AURA2 is best described in Goss et al. 2018.

Biomarker eligibility criteria

Targeted therapy

Continued indefinitely


Regimen variant #2, 160 mg/day

Study Dates of enrollment Evidence Efficacy
Yang et al. 2019 (BLOOM) 2015-2017 Phase 1, >20 pts BICR- LM ORR (62%), DoR 15.2 months

Investigator- LM ORR (41%), DoR 8.3 months

Patients with leptomeningeal metastases (LMs) from EGFR-mutated (EGFRm) advanced non-small-cell lung cancer (NSCLC) whose disease had progressed on previous EGFR-TKI therapy. BICR- Blinded Independent Central Review, DoR- Duration of Response, ORR-Objective response rate

Biomarker eligibility criteria

Targeted therapy

Continued indefinitely

References

  1. AURA: Jänne PA, Yang JC, Kim DW, Planchard D, Ohe Y, Ramalingam SS, Ahn MJ, Kim SW, Su WC, Horn L, Haggstrom D, Felip E, Kim JH, Frewer P, Cantarini M, Brown KH, Dickinson PA, Ghiorghiu S, Ranson M. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N Engl J Med. 2015 Apr 30;372(18):1689-99. link to original article contains dosing details in manuscript PubMed NCT01802632
    1. Update: Yang JC, Ahn MJ, Kim DW, Ramalingam SS, Sequist LV, Su WC, Kim SW, Kim JH, Planchard D, Felip E, Blackhall F, Haggstrom D, Yoh K, Novello S, Gold K, Hirashima T, Lin CC, Mann H, Cantarini M, Ghiorghiu S, Jänne PA. Osimertinib in Pretreated T790M-Positive Advanced Non-Small-Cell Lung Cancer: AURA Study Phase II Extension Component. J Clin Oncol. 2017 Apr 20;35(12):1288-1296. Epub 2017 Feb 21. link to original article PubMed
    2. Pooled subgroup analysis: Goss G, Tsai CM, Shepherd FA, Ahn MJ, Bazhenova L, Crinò L, de Marinis F, Felip E, Morabito A, Hodge R, Cantarini M, Johnson M, Mitsudomi T, Jänne PA, Yang JC. CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. Ann Oncol. 2018 Mar 1;29(3):687-693. link to original article PubMed NCT01802632
    3. Pooled update: Ahn MJ, Tsai CM, Shepherd FA, Bazhenova L, Sequist LV, Hida T, Yang JCH, Ramalingam SS, Mitsudomi T, Jänne PA, Mann H, Cantarini M, Goss G. Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: Long-term follow-up from a pooled analysis of 2 phase 2 studies. Cancer. 2019 Mar 15;125(6):892-901. Epub 2018 Dec 4. link to original article PubMed
  2. AURA2: Goss G, Tsai CM, Shepherd FA, Bazhenova L, Lee JS, Chang GC, Crino L, Satouchi M, Chu Q, Hida T, Han JY, Juan O, Dunphy F, Nishio M, Kang JH, Majem M, Mann H, Cantarini M, Ghiorghiu S, Mitsudomi T. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2016 Dec;17(12):1643-1652. Epub 2016 Oct 14. link to original article PubMed NCT02094261
    1. Pooled subgroup analysis: Goss G, Tsai CM, Shepherd FA, Ahn MJ, Bazhenova L, Crinò L, de Marinis F, Felip E, Morabito A, Hodge R, Cantarini M, Johnson M, Mitsudomi T, Jänne PA, Yang JC. CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. Ann Oncol. 2018 Mar 1;29(3):687-693. link to original article PubMed
    2. Pooled update: Ahn MJ, Tsai CM, Shepherd FA, Bazhenova L, Sequist LV, Hida T, Yang JCH, Ramalingam SS, Mitsudomi T, Jänne PA, Mann H, Cantarini M, Goss G. Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: Long-term follow-up from a pooled analysis of 2 phase 2 studies. Cancer. 2019 Mar 15;125(6):892-901. Epub 2018 Dec 4. link to original article PubMed
  3. AURA3: Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, Shepherd FA, He Y, Akamatsu H, Theelen WS, Lee CK, Sebastian M, Templeton A, Mann H, Marotti M, Ghiorghiu S, Papadimitrakopoulou VA; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017 Feb 16;376(7):629-640. Epub 2016 Dec 6. link to original article contains dosing details in manuscript link to PMC article PubMed NCT02151981
    1. PRO analysis: Lee CK, Novello S, Rydén A, Mann H, Mok T. Patient-Reported Symptoms and Impact of Treatment With Osimertinib Versus Chemotherapy in Advanced Non-Small-Cell Lung Cancer: The AURA3 Trial. J Clin Oncol. 2018 Jun 20;36(18):1853-1860. Epub 2018 May 7. link to original article PubMed
    2. Subgroup analysis: Wu YL, Ahn MJ, Garassino MC, Han JY, Katakami N, Kim HR, Hodge R, Kaur P, Brown AP, Ghiorghiu D, Papadimitrakopoulou VA, Mok TSK. CNS efficacy of osimertinib in patients with T790M-positive advanced non-small-cell lung cancer: data from a randomized phase III trial (AURA3). J Clin Oncol. 2018 Sep 10;36(26):2702-2709. Epub 2018 Jul 30. link to original article PubMed
    3. Update: Papadimitrakopoulou VA, Mok TS, Han JY, Ahn MJ, Delmonte A, Ramalingam SS, Kim SW, Shepherd FA, Laskin J, He Y, Akamatsu H, Theelen WSME, Su WC, John T, Sebastian M, Mann H, Miranda M, Laus G, Rukazenkov Y, Wu YL. Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis. Ann Oncol. 2020 Nov;31(11):1536-1544. Epub 2020 Aug 27. link to original article PubMed
  4. FLAURA: Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F, Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y, Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM, Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. Epub 2017 Nov 18. link to original article contains dosing details in manuscript PubMed NCT02296125
    1. Subgroup analysis: Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK, Bertolini A, Bohnet S, Zhou C, Lee KH, Nogami N, Okamoto I, Leighl N, Hodge R, McKeown A, Brown AP, Rukazenkov Y, Ramalingam SS, Vansteenkiste J. CNS response to osimertinib versus standard epidermal growth factor receptor tyrosine kinase inhibitors in patients with untreated EGFR-mutated advanced non-small-cell lung cancer. J Clin Oncol. 2018 Nov 20;36(33):3290-7. Epub 2018 Aug 28. link to original article PubMed
  5. BLOOM: Yang JCH, Kim SW, Kim DW, Lee JS, Cho BC, Ahn JS, Lee DH, Kim TM, Goldman JW, Natale RB, Brown AP, Collins B, Chmielecki J, Vishwanathan K, Mendoza-Naranjo A, Ahn MJ. Osimertinib in Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study. J Clin Oncol. 2020 Feb 20;38(6):538-547. Epub 2019 Dec 6. link to original article link to PMC article PubMed NCT02228369
  6. WJOG9116L: Yamaguchi H, Wakuda K, Fukuda M, Kenmotsu H, Mukae H, Ito K, Chibana K, Inoue K, Miura S, Tanaka K, Ebi N, Suetsugu T, Harada T, Kirita K, Yokoyama T, Nakatani Y, Yoshimura K, Nakagawa K, Yamamoto N, Sugio K. A Phase II Study of Osimertinib for Radiotherapy-Naive Central Nervous System Metastasis From NSCLC: Results for the T790M Cohort of the OCEAN Study (LOGIK1603/WJOG9116L). J Thorac Oncol. 2021 Dec;16(12):2121-2132. Epub 2021 Aug 19. link to original article contains dosing details in abstract PubMed UMIN000024218
Retrieved from "https://hemonc.org/w/index.php?title=Non-small_cell_lung_cancer,_CNS_metastases&oldid=83972"